Therapeutic compound for pain and synthesis thereof

ABSTRACT

The invention provides compounds of Formula XXIII: 
                         
wherein R 1  is hydrogen, alkyl, acyl, or silyl, R 2  is hydrogen, alkyl, benzyl, acyl, or ester, and R 3  is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl, heteroalkyl, acyl, or ester, as well as derivatives and stereoisomers, pharmaceutically acceptable salts and derivatives thereof; and methods of making and using such compounds. The invention includes pharmaceutical compositions containing such compounds, and the use of such compounds in methods of treating conditions, diseases, or disorders.

RELATED APPLICATIONS

This patent application claims the benefit of U.S. ProvisionalApplication Ser. No. 62/214,727, filed Sep. 4, 2015, and U.S.Provisional Application Ser. No. 62/214,734, filed Sep. 4, 2015, each ofwhich is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The invention provides new pharmaceutically active chemical compounds,which can be used for treating conditions and disorders in animals,mammals, and humans.

BACKGROUND

New chemical compounds having pharmaceutical activity can be indicatedfor the treatment of previously untreatable conditions, better treatmentof conditions than can be achieved with conventional pharmaceuticalcompounds, and treatment of conditions that were previously treatablewith conventional pharmaceutical compounds, but now are no longereffectively treatable.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula XXIII:

wherein R₁ is hydrogen, alkyl, acyl, or silyl, R₂ is hydrogen, alkyl,benzyl, acyl, or ester, and R₃ is hydrogen, alkyl, an aromatic group,azacyclic, carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle,heteroaryl, heteroalkyl, acyl, or ester, as well as derivatives andstereoisomers thereof.

In some embodiments, one or more of the R₁, R₂ and R₃ groups areoptionally substituted with one or more substituents. In variousembodiments, the optional substituents are selected from halo, ═O,═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′,NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂, OOCR′, COR′, and NO₂,wherein each R′ is independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of which is optionallysubstituted with one or more groups selected from halo, C₁-C₄ alkyl,C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy, amino, and ═O;wherein two R′ can be linked to form a 3-7 membered ring optionallycontaining up to three heteroatoms selected from N, O and S.

In specific embodiments, R₃ is an optionally substituted aryl methylgroup or an optionally substituted heteroaryl methyl group.

In certain embodiments, the invention includes a pharmaceuticalcomposition containing a compound of Formula XXIII and/or a derivativethereof. In one embodiment, the invention includes a pharmaceuticalcomposition comprising a compound of Formula XXIII and/or a derivativealong with a pharmaceutically acceptable carrier or diluent. In anotherembodiment, the invention provides a method for treating a subject (ahuman or an animal) suffering from a condition, disease, or disorder,comprising administering to the subject an effective amount of acompound of Formula XXIII or a derivative thereof. In one embodiment,the compound is administered to effect localized delivery to thesubject. In another embodiment, the compound is administered to effectsystemic delivery to the subject. In a further embodiment, a compound ofFormula XXIII, or a derivative thereof, is used as a medicament, or usedin the manufacture of a medicament. In some embodiments, the conditionor disorder is pain. In specific embodiments, the pain is neuropathicpain or chronic pain.

In certain embodiments, R₃ is trifluoroacyl.

In certain embodiments R₁ is tert-butyldiphenylsylyl, R₂ is hydrogen,and R₃ is —COOR₄, where R₄ is selected from the group consisting ofalkyl and benzyl. In further embodiments, R₄ is benzyl, in otherembodiments, R₄ is alkyl having 1 to 8 carbon atoms. In still furtherembodiments, R₄ is ethyl. In other embodiments, R₄ is tert-butyl.

The present invention provides compounds of Formula XXIII(A):

wherein R₄ is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle,aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester; R₂ is hydrogen, alkyl, benzyl, acyl, orester, and R₃ is hydrogen, alkyl, an aromatic group, azacyclic,carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester, as well as derivatives and stereoisomersthereof.

In some embodiments, R₄ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₂ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₃ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

The present invention provides compounds of Formula XXIII(B):

wherein R₅ is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle,aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester; R₁ is hydrogen, alkyl, benzyl, acyl, orester, and R₃ is hydrogen, alkyl, an aromatic group, azacyclic,carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester, as well as derivatives and stereoisomersthereof.

In some embodiments, R₅ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₁ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₃ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

The present invention provides compounds of Formula XXIII(C):

wherein R₄ is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle,aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester; R₅ is hydrogen, alkyl, benzyl, acyl, orester, and R₃ is hydrogen, alkyl, an aromatic group, azacyclic,carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester, as well as derivatives and stereoisomersthereof.

In some embodiments, R₄ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₅ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₃ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

The present invention provides compounds of Formula XXIII(D):

wherein R₁ is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle,aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester; R₂ is hydrogen, alkyl, benzyl, acyl, orester, and R₆ is hydrogen, alkyl, an aromatic group, azacyclic,carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester, as well as derivatives and stereoisomersthereof.

In some embodiments, R₄ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₅ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₆ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

The present invention provides compounds of Formula XXIII(E):

wherein R₄ is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle,aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester; R₅ is hydrogen, alkyl, benzyl, acyl, orester, and R₆ is hydrogen, alkyl, an aromatic group, azacyclic,carbocycle, aryl, cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl,heteroalkyl, acyl, or ester, as well as derivatives and stereoisomersthereof.

In some embodiments, R₄ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₅ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

In some embodiments, R₆ is optionally substituted with one or moresubstituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂,SR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CON(R′)₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,C₁-C₆ alkyl, C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl,each of which is optionally substituted with one or more groups selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl,hydroxy, amino, and ═O; wherein two R′ can be linked to form a 3-7membered ring optionally containing up to three heteroatoms selectedfrom N, O and S.

The present invention provides compounds of the Formula I:

(2R,3S,6S,7aS)-tert-butyl 3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate andstereoisomers thereof. That is, a compound of Formula I can have theFormula I.a:

((2R*,3R*,3aS*,6S*,7aS*)-)-tert-butyl 3-((tertbutyldiphenylsilyl)oxy)-octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)or the Formula I.b:

((2S*,3R*,3aS*,6R*,7aR*)-tert-butyl3-((tertbutyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)where Boc is tert-butyloxycarbonyl and TBDPS istert-butyldiphenylsilane.

A quantity of a compound of Formula I can be enantiomerically pure andconsist entirely of the enantiomers of Formula I.a or the enantiomer ofFormula I.b. Alternatively, it can comprise a mixture of theenantiomers, which may contain equal amounts of the enantiomer ofFormula I.a and the enantiomer of Formula I.b, or be a mixture havingdiffering amounts of each of the enantiomer of Formula I.a or theenantiomer of Formula I.b.

In certain embodiments, the invention includes a pharmaceuticalcomposition containing a compound of Formula I and/or a derivativethereof. In one embodiment, the invention includes a pharmaceuticalcomposition comprising a compound of Formula I and/or derivative thereofand a pharmaceutically acceptable carrier or diluent. In anotherembodiment, the invention provides a method for treating a subject (ahuman or an animal) suffering from a condition, disease, or disorder,comprising administering to the subject an effective amount of acompound of Formula I and/or derivative thereof. In one embodiment, thecompound is administered to effect localized delivery to the subject. Inanother embodiment, the compound is administered to effect systemicdelivery to the subject. In a further embodiment, a compound of FormulaI, and/or derivative thereof is used as a medicament, or used in themanufacture of a medicament. In some embodiments, the condition ordisorder is pain. In specific embodiments, the pain is neuropathic painor chronic pain.

The present invention also provides methods of making a compound ofFormula I.a or Formula I.b by chirally separating a racemic mixture ofcompounds of Formula I.

In other embodiments, the method includes making the compound of FormulaI. In one such embodiment, the method of making the compound of FormulaI includes reacting a compound of Formula II:

rac-(2R,3R,6S,7aS)-tert-butyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith hydrogen. The reaction may be performed in the presence of acatalyst. In a preferred embodiment, the catalyst includes palladium.For example, the catalyst can be palladium on carbon.

In other embodiments, the method includes making the compound of FormulaII. In one such embodiment, the method of making the compound of FormulaII includes reacting a compound of Formula III:

rac-(2R,3R,6S,7aS)-4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridinewith di-tert-butyl dicarbonate (Boc₂O) to add a tert-butyloxycarbonyl(Boc) protecting group. In a preferred embodiment the reaction furthercomprises triethylamine (Et₃N).

In other embodiments, the method also includes making the compound ofFormula III. In one such embodiment, the method of making the compoundof Formula III includes reacting a compound of Formula IV:

(2R,3R,6S,7aS)-ethyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith iodotrimethylsilane.

In other embodiments, the method also includes making the compound ofFormula IV. In one such embodiment, the method of making the compound ofFormula IV includes reacting a compound of Formula V:

(2R,3S,6S,7aS)-ethyl-4-benzyl-3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith TBDPS. In a preferred embodiment the reaction further comprisesimidazole.

In other embodiments, the method also includes making the compound ofFormula V. In one such embodiment, the method of making the compound ofFormula V includes reacting a compound of Formula VI:

(2R,3 S,6S,7aS)-ethyl3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylatewith benzaldehyde. In a preferred embodiment the reaction furthercomprises sodium triacetoxyborohydride (STAB).

In other embodiments, the method also includes making the compound ofFormula VI. In one such embodiment, the method of making the compound ofFormula VI includes cyclizing a compound of Formula VI.a:

(1R,2R,4S,5S,7s)-ethyl7-(aminomethyl)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate in asolvent. The solvent can be ethanol (EtOH).

In other embodiments, the method also includes making the compound ofFormula VI.a. In one such embodiment, the method of making the compoundof Formula VI.a includes reacting a compound of Formula VII:

(1R,2R,4S,5 S,7s)-ethyl7-cyano-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate withhydrogen. The reaction may be performed in the presence of a catalyst.In one embodiment, the catalyst includes nickel. For example, thecatalyst can be Raney-nickel.

In other embodiments, the method also includes making the compound ofFormula VII. In one such embodiment, the method of making the compoundof Formula VII includes reacting a compound of Formula VIII:

(1R,2R,4S,5S,7r)-ethyl7-((methylsulfonyl)oxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylatewith potassium cyanide. In other embodiments the reaction furthercomprises 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane).

In other embodiments, the method also includes making the compound ofFormula VIII. In one such embodiment, the method of making the compoundof Formula VIII includes reacting a compound of Formula IX:

(1R,2R,4S,5S,7r)-ethyl7-hydroxy-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate with mesylchloride. In a preferred embodiment the reaction further comprisestriethylamine (ET₃N).

In other embodiments, the method also includes making the compound ofFormula IX. In one such embodiment, the method of making the compound ofFormula IX includes reacting a compound of Formula X:

(1R,2R,4S,5S,7r)-ethyl7-(benzoyloxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate witha reducing agent. The reducing agent can be sodium borohydride.

In other embodiments, the method also includes making the compound ofFormula X. In one such embodiment, the method of making the compound ofFormula X includes reacting a compound of Formula XI:

(1R,2R,4S,5S,7r)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ylbenzoate with ethyl chloroformate. In a preferred embodiment thereaction further comprises a base. The base can be potassium carbonate.

In other embodiments, the method also includes making the compound ofFormula XI. In one such embodiment, the method of making the compound ofFormula XI includes reacting a compound of Formula XII:

(1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol) withbenzoic acid in the presence of an activating agent. The activatingagent can be diethylazodicaroxylate (DEAD) with triphenylphosphine(PPh₃) or diisopropyl azodicarboxylate (DIAD) with PPh₃.

In other embodiments, the method also includes making the compound ofFormula XII. In one such embodiment, the method of making the compoundof Formula XII includes reacting a compound of Formula XIII:

(2S)-(1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl-3-hydroxy-2-phenylpropanoatehydrobromide trihydrate (scopolamine) with a reducing agent. Thereducing agent can be sodium borohydride. In a preferred embodiment thereaction further comprises HCl in isopropyl alcohol.

In a further embodiment the invention provides a compound of FormulaXVIII:

((2R*,3R*,3aS*,6S*,7aS*)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylcyclopropanecarboxylate).

In certain embodiments, the invention includes a pharmaceuticalcomposition containing a compound of Formula XVIII and/or a derivativethereof. In one embodiment, the invention includes a pharmaceuticalcomposition comprising a compound of Formula XVIII and apharmaceutically acceptable carrier or diluent. In another embodiment,the invention provides a method for treating a subject (a human or ananimal) suffering from a condition, disease, or disorder, comprisingadministering to the subject an effective amount of a compound ofFormula XVIII. In one embodiment, the compound is administered to effectlocalized delivery to the subject. In another embodiment, the compoundis administered to effect systemic delivery to the subject. In a furtherembodiment, a compound of Formula XVIII is used as a medicament, or usedin the manufacture of a medicament. In some embodiments, the conditionor disorder is pain, including but not limited to neuropathic pain andchronic pain.

An embodiment of the invention provides a method of making a compound ofFormula XVIII including reacting a compound of Formula XVII:

((2R*,3R*,3aS*,6S*,7aS*)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylcyclopropanecarboxylate) with piperonal. The reaction can be performedin the presence of a reducing agent. For example, the reducing agent canbe STAB.

The method can also include making the compound of Formula XVII. In anembodiment, the method of making the compound of Formula XVII includesremoving and replacing the Boc group from a compound of Formula XVI,with hydrogen:

((2R*,3R*,3aS,6S,7aS*)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylcyclopropanecarboxylate). The Boc group can be removed with an acid. Forexample, the acid can be trifluoracetic acid (TFA).

The method can also include making the compound of Formula XVI. In anembodiment, the method of making the compound of Formula XVI includesreacting a compound of Formula XV:

((2R*,3R*,3 aS*,6S*,7aS*)-tert-butyl4-(5-fluoropicolinoyl)-3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)with cyclopropanecarbonyl chloride. The reaction can be performed in thepresence of a nucleophilic catalyst. For example, the nucleophiliccatalyst can be 4-dimethylaminopyridine (DMAP).

The method can also include making the compound of Formula XV. In anembodiment, the method of making the compound of Formula XV includesremoving the TBDPS group from a compound of Formula XIV, and replacingit with a hydrogen:

((2R*,3R*,3 aS*,6S*,7aS*)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).For example, the TBPDS group can be removed with tetrabutylammoniumfluoride (TBAF).

The method can also include making the compound of Formula XIV. In anembodiment, the method of making the compound of Formula XIV includesreacting a compound of Formula I.a, with 5-fluoropicolinic acid. In apreferred embodiment the reaction further comprises 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA).

In a further embodiment the invention provides a compound of FormulaXXII:

3-(((2S*,3S*,6R*,7aR*)-3-hydroxy-4-(2-methoxyacetyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-1-yl)methyl)benzamide.

In certain embodiments, the invention includes a pharmaceuticalcomposition containing a compound of Formula XXII and/or a derivativethereof. In one embodiment, the invention includes a pharmaceuticalcomposition comprising a compound of Formula XXII and a pharmaceuticallyacceptable carrier or diluent. In another embodiment, the inventionprovides a method for treating a subject (a human or an animal)suffering from a condition, disease, or disorder, comprisingadministering to the subject an effective amount of a compound ofFormula XXII. In one embodiment, the compound is administered to effectlocalized delivery to the subject. In another embodiment, the compoundis administered to effect systemic delivery to the subject. In a furtherembodiment, a compound of Formula XXII is used as a medicament, or usedin the manufacture of a medicament. In some embodiments, the conditionor disorder is pain. In specific embodiments, the pain is neuropathicpain or chronic pain.

An embodiment of the invention provides a method of making a compound ofFormula XXII including reacting a compound of Formula XXI:

1-((2S*,3S*,3aS*,6R*,7aR*)-3-hydroxyhexahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-4(2H)-yl)-2-methoxyethanone)with 3-formyl benzamide. The reaction can further be performed in thepresence of a reducing agent. For example, the reducing agent can beSTAB.

The method can also include making the compound of Formula XXI. In anembodiment, the method of making the compound of Formula XXI includesremoving the Boc group from a compound of Formula XX, and replacing itwith hydrogen:

((2S*,3 S*,3 aS*,6R*,7aR*)-tert-butyl3-hydroxy-4-(2-methoxyacetyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).The Boc group can be removed with an acid. For example, the acid can beTFA.

The method can also include making the compound of Formula XX. In anembodiment, the method of making the compound of Formula XX includesremoving the TBDPS group from a compound of Formula XIX, and replacingit with hydrogen:

((2 S*,3 S*,6R*,7aR*)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)-4-(2-methoxyacetyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).For example, the TBPDS group can be removed with TBAF.

The method can also include making the compound of Formula XIX. In anembodiment, the method of making the compound of Formula XIX includesreacting a compound of Formula I.b, with 2-methoxyacetic acid. Thereaction can further be performed with HATU and DIPEA.

BRIEF DESCRIPTION OF THE DRAWINGS

The preceding Summary, as well as the following Detailed Description ofthe invention, can be better understood when read in conjunction withthe appended Figures. For the purpose of illustrating the invention, theFigures demonstrate embodiments of the present invention. However, itshould be understood that the invention is not limited to the precisearrangements, examples, and instrumentalities shown.

FIG. 1 shows the results of a ^(1H)NMR analysis of the compound ofFormula XII.

FIG. 2 shows the results of a MS analysis of the compound of Formula XI.

FIGS. 3A and 3B show the results of a structural analysis of thecompound of Formula X. FIG. 3A shows the results of a ^(1H)NMR analysisof the compound of Formula X. FIG. 3B shows the results of a MS analysisof the compound of Formula X.

FIG. 4 shows the results of a ^(1H)NMR analysis of the compound ofFormula IX.

FIG. 5 shows the results of a ^(1H)NMR analysis of the compound ofFormula VIII.

FIG. 6 shows the results of a ^(1H)NMR analysis of the compound ofFormula VII

FIG. 7 shows the results of a ^(1H)NMR analysis of the compound ofFormula VI.

FIGS. 8A and 8B show the results of a structural analysis of thecompound of Formula V. FIG. 8A shows the results of a MS analysis of thecompound of Formula V. FIG. 8B shows the results of a ^(1H)NMR analysisof the compound of Formula V.

FIGS. 9A and 9B show the results of a structural analysis of thecompound of Formula IV. FIG. 9A shows the results of a LCMS analysis ofthe compound of Formula IV. FIG. 9B shows the results of a ^(1H)NMRanalysis of the compound of Formula IV.

FIG. 10 shows the results of a LCMS analysis of the compound of FormulaIII.

FIGS. 11A and 11B show the results of a structural analysis of thecompound of Formula II. FIG. 11A shows the results of a ^(1H)NMRanalysis of the compound of Formula II. FIG. 11B shows the results of aLCMS analysis of the compound of Formula II.

FIGS. 12A and 12B show the results of a structural analysis of thecompound of Formula I. FIG. 12A shows the results of a LCMS analysis ofthe compound of Formula I. FIG. 12B shows the results of a ^(1H)NMRanalysis of the compound of Formula I.

FIG. 13 shows the results of a LCMS analysis of the compound of FormulaXIV.

FIG. 14 shows the results of a LCMS analysis of the compound of FormulaXV.

FIG. 15 shows the results of a LCMS analysis of the compound of FormulaXVI.

FIG. 16 shows the results of a LCMS analysis of the compound of FormulaXVII.

FIGS. 17A and 17B show the results of a structural analysis of thecompound of Formula XVIII. FIG. 17A shows the results of a LCMS analysisof the compound of Formula XVIII. FIG. 17B shows the results of a^(1H)NMR analysis of the compound of Formula XVIII.

FIG. 18 shows the results of a LCMS analysis of the compound of FormulaXIX.

FIG. 19 shows the results of a LCMS analysis of the compound of FormulaXX.

FIG. 20 shows the results of a LCMS analysis of the compound of FormulaXXI.

FIGS. 21A and 21B show the results of a structural analysis of thecompound of Formula XXII. FIG. 21A shows the results of a LCMS analysisof the compound of Formula XXII. FIG. 21B shows the results of a^(1H)NMR analysis of the compound of Formula XXII.

DETAILED DESCRIPTION

Embodiments of the invention are discussed in detail below. Indescribing these embodiments, specific terminology is employed for thesake of clarity. However, the invention is not intended to be limited tothe specific terminology selected. A person skilled in the relevant artwill recognize that other equivalent parts can be employed and othermethods developed without parting from the spirit and scope of theinvention.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers to a divalent alkyl radical. Any of the abovementioned monovalent alkyl groups may be an alkylene by abstraction of asecond hydrogen atom from the alkyl. In some embodiments, an alkelene isa C₁-C₆alkylene. In other embodiments, an alkylene is a C₁-C₄alkylene.Typical alkylene groups include, but are not limited to, —CH₂—,—CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, and the like.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain and having at least one ofthe hydrogens replaced with a halogen. In some embodiments, a haloalkylgroup is a C₁-C₆ haloalkyl group. In some embodiments, a haloalkyl groupis a C₁-C₄ haloalkyl group. One exemplary substitutent is fluoro.Preferred substituted alkyl groups of the invention includetrihalogenated alkyl groups such as trifluoromethyl groups. Haloalkylincludes and is not limited to CF₃, CH₂F, —CHF₂, —CH₂Cl, —CH₂—CF₃, andthe like.

The term “alkoxy” includes a straight chain or branched alkyl group witha terminal oxygen linking the alkyl group to the rest of the molecule.In some embodiments, an alkoxy group is a C₁-C₆ alkoxy group. In someembodiments, an alkoxy group is a C₁-C₄ alkoxy group. Alkoxy includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and soon.

The term “heterocycle” represents a mono- or bi-cyclic hydrocarbon ringstructure optionally containing heteroatoms selected from O, S, and N.Heterocyclyl rings can have 2 to 10 carbon atoms in the ring.

“Azacyclic” or “azacyclic ring” refers to a saturated, partiallyunsaturated, or aromatic 3-7 membered monocyclic ring or an 8-12membered fused bicyclic ring system containing at least one nitrogenatom. Such azacyclic rings may optionally contain from 1-2 additionalheteroatoms selected from N, O, and S as ring members, and mayoptionally be substituted to the extent such substitutions make chemicalsense.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a C₆-C₁₀aryl. Depending on the structure, anaryl group is a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 3 to 10 atoms in its ringsystem, and with the proviso that any ring does not contain two adjacentO or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include rings having 3 to 10 atoms in its ring systemand aromatic heterocyclic groups include rings having 5 to 10 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl,isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused withan aryl or heteroaryl. In some embodiments, the heterocycloalkyl isoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidin-2-onyl,pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The termheteroalicyclic also includes all ring forms of the carbohydrates,including but not limited to the monosaccharides, the disaccharides andthe oligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

A wavy line “

” indicates the point of attachment to the rest of the molecule.

“Benzyl” and —CH₂-phenyl are used interchangeably.

The term “acyl” is used herein as is conventional in the field oforganic chemistry. For example, “acyl” can denote a carbonyl group witha bonded alkyl group.

The term “ester” is used herein as is conventional in the field oforganic chemistry. For example, the term “ester” can denote a carbonylgroup with a bonded oxygen and alkyl or an oxygen with a bonded carbonyland alkyl.

The term “silyl” is used herein as is conventional in the field oforganic chemistry. For example, the term “silyl” can denote a siliconatom to which hydrogen and/or alkyl groups can be bonded.

As used herein, the term “Boc-protection” denotes functionalization of achemical compound with a tert-butyloxycarbonyl (Boc) group as aprotecting group. This allows the chemical compound as a whole to betreated with reagents that would otherwise undesirably attack theunprotected group. The protected group can thereafter be deprotected toyield the desired original group.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered. A “pharmaceutically acceptable excipient” refers to asubstance that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to a subject, such as an inertsubstance, added to a pharmacological composition or otherwise used as avehicle, carrier, or diluent to facilitate administration of a agent andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

In treatment methods according to the invention, a therapeuticallyeffective amount of a pharmaceutical agent according to the invention isadministered to a subject suffering from or diagnosed as having such adisease, disorder, or condition. A “therapeutically effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic or prophylactic benefit in patients in need of suchtreatment for the designated disease, disorder, or condition.

Effective amounts or doses of the compounds of the present invention maybe ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the compound, the severity and course of thedisease, disorder, or condition, the subject's previous or ongoingtherapy, the subject's health status and response to drugs, and thejudgment of the treating physician. An example of a dose is in the rangeof from about 0.001 to about 200 mg of compound per kg of subject's bodyweight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). Fora 70-kg human, an illustrative range for a suitable dosage amount isfrom about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

“Compounds of the present invention,” and equivalent expressions, aremeant to embrace compounds of the Formula as described herein, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g., hydrates, where the context so permits. Similarly,reference to intermediates, whether or not they themselves are claimed,is meant to embrace their salts, and solvates, where the context sopermits.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can be radiolabeled, that is, contain one or morenon-radioactive or radioactive isotopes, such as for example, deuterium(²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will beunderstood that, in a compound where such isotopic substitution is made,the following atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art. Likewise, the invention may include thepreparation of isotopic variants with radioisotopes, in the instance forexample, where the resulting compounds may be used for drug and/orsubstrate tissue distribution studies. Radiolabeled compounds of theinvention can be used in diagnostic methods such as Single-photonemission computed tomography (SPECT). The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for their easeof incorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the invention, radioactive ornot, are intended to be encompassed within the scope of the invention.In one aspect, provided herein are deuterated or tritiated analogs ofcompounds described.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

As used herein, the term “triturate” denotes a method of purifying amaterial in which the crude material is washed with a solvent. Thesolvent can be selected, so that the desired product is insoluble andthe impurities are soluble, in which case, the purified product is leftin solid form and the impurities are removed with the solvent.Conversely, the solvent can be selected, so that the desired product issoluble and the impurities are insoluble, in which case, the purifiedproduct is in solution and the impurities are removed as solids. Thesolvent can then be removed, for example, through evaporation, to obtainthe purified product.

Compounds of the invention may also exist as “rotamers,” that is,conformational isomers that occur when the rotation leading to differentconformations is hindered, resulting a rotational energy barrier to beovercome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

As used herein, the term “localized delivery” denotes delivery of apharmaceutical or therapeutic agent to a specific, limited region of thebody.

As used herein, the term “systemic delivery” denotes delivery of apharmaceutical or therapeutic agent throughout the body, for example,through administration to the circulatory system.

As used herein, the term “mass spectrometry (MS)” denotes an analytictechnique that ionizes a chemical compound to generate charged moleculesor molecule fragments and measures their abundance as a function ofmass-to-charge (m/z) ratio (the mass spectrum). From the mass spectrum,conclusions as to the structure of the chemical compound can be drawn.

As used herein, the term “liquid chromatography-mass spectrometry(LCMS)” denotes an analytic technique that combines the physicalseparation capability of liquid chromatography with the analyticcapability of mass spectrometry. In the liquid chromatography step, thesample is introduced into a column packed with a stationary phase,separating the chemical compounds of the sample by their retention time(Rt) in the column. The chemical compound or compounds associated with aretention time interval are then directed to a mass spectrometer, toobtain a mass spectrum that allows conclusions as to the structure ofthis chemical compound or compounds to be drawn.

As used herein, the term “thin-layer chromatography (TLC)” denotes ananalytic technique that separates chemical compounds in a sample by thedifferent rates in which they are drawn up a plate coated with astationary phase material.

As used herein, the term “nuclear magnetic resonance spectroscopy (NMR)”denotes an analytic technique that measures the intensity of a resonanceresponse of a set of nuclei to a radio frequency pulse to allowinformation as to the electronic environment of the nuclei to beobtained. From this, conclusions can be drawn as to the chemicalstructure of the compound in which the nuclei reside. A nuclear magneticresonance spectroscopy technique that uses hydrogen nuclei (protons) istermed proton nuclear magnetic resonance spectroscopy (^(1H)NMR).

The present invention provides compounds of the Formula XXIII:

wherein R₁ is hydrogen, alkyl, acyl, or silyl;R₂ is hydrogen, alkyl, benzyl, acyl, or ester; andR₃ is hydrogen, alkyl, an aromatic group, azacyclic, carbocycle, aryl,cycloalkyl, heterocycloalkyl, heterocycle, heteroaryl, heteroalkyl,acyl, or ester, as well as derivatives and stereoisomers thereof.

In some embodiments, R₁ is optionally substituted with one or moresubstituents. In various embodiments, the optional substituents areselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S.

In some embodiments, R₂ is optionally substituted with one or moresubstituents. In various embodiments, the optional substituents areselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S.

In some embodiments, R₃ is optionally substituted with one or moresubstituents. In various embodiments, the optional substituents areselected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, N(R′)₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CON(R′)₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; wherein two R′ can be linked to form a 3-7 membered ringoptionally containing up to three heteroatoms selected from N, O and S.

The present invention provides a compound having the structure ofFormula I:

(2R,3S,6S,7aS)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate,and stereoisomers thereof. This compound can be prepared by the reactionsequences described in Schemes 1-13 set forth in Example 1.

The present invention further provides therapeutic derivatives of thecompound of Formula I, and methods for their synthesis. One suchderivative is the compound of the Formula XVIII:

((2R*,3R*,3aS*,6S*,7aS*)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylcyclopropanecarboxylate). This compound can be prepared by the reactionsequences described in Schemes 15-19 set forth in Example 2.

A second therapeutic derivative of the compound of Formula I is thecompound of the Formula XXII:

This compound can be prepared by the reaction sequences described inschemes 20-23 set forth in Example 3.Pharmaceutical Compositions and Administration

The compounds of the present invention are useful as pharmaceuticalagents and can be incorporated into pharmaceutical compositionscomprising a therapeutically effective amount of a compound of theinvention, as defined herein, and a pharmaceutically acceptable carrieror diluent.

The compounds of the invention can also be used in the manufacture ofderivative compounds that are useful as pharmaceutical agents, and whichcan likewise be incorporated into pharmaceutical compositions preparedwith a therapeutically effective amount of such a derivative compoundand a pharmaceutically acceptable carrier or diluent.

The compounds of the invention, and such derivatives thereof, can beuseful in the treatment of conditions, diseases, and disorders in humansand animals. Such compounds can be formulated as pharmaceuticalcompositions and administered to a subject in need of treatment, forexample a mammal, such as a human patient, in a variety of forms adaptedto the chosen route of administration. For example compounds of theinvention may be formulated for administration, orally, nasally,intraperitoneally, or parenterally, by intravenous, intramuscular,topical, or subcutaneous routes, or by injection into tissue.

Thus, compounds of the invention may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier, or by inhalationor insufflation. They may be enclosed in hard or soft shell gelatincapsules, may be compressed into tablets, or may be incorporateddirectly with the food of the patient's diet. For oral therapeuticadministration, the compounds may be combined with one or moreexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.The compounds may be combined with an inert powdered carrier and inhaledby the subject or insufflated. Such compositions and preparations shouldcontain at least 0.1% of a compound of the present invention. Thepercentage of the compound of the invention present in such compositionsand preparations may, of course, be varied and may conveniently bebetween about 2% to about 60% of the weight of a given unit dosage form.The amount of the compound in such therapeutically useful compositionsis such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid, and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose, or aspartame, or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or for otherwise modifying the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac, or sugar, and the like. A syrup or elixirmay contain the active compound, sucrose or fructose as a sweeteningagent, methyl and propylparabens as preservatives, a dye, and flavoringsuch as cherry or orange flavor. Of course, any material used inpreparing any unit dosage form should be pharmaceutically acceptable andsubstantially non-toxic in the amounts employed. In addition, thecompounds may be incorporated into sustained-release preparations anddevices. For example, the compounds may be incorporated into timerelease capsules, time release tablets, time release pills, and timerelease polymers or nanoparticles.

The compounds may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the compoundscan be prepared in water, optionally mixed with a nontoxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, triacetin, and mixtures thereof, and in oils. Under ordinaryconditions of storage and use, these preparations can contain apreservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the compounds which are adapted for the extemporaneouspreparation of sterile injectable or infusible solutions or dispersions,optionally encapsulated in liposomes. In all cases, the ultimate dosageform should be sterile, fluid, and stable under the conditions ofmanufacture and storage. The liquid carrier or vehicle can be a solventor liquid dispersion medium comprising, for example, water, ethanol, apolyol (for example, glycerol, propylene glycol, liquid polyethyleneglycols, and the like), vegetable oils, nontoxic glyceryl esters, andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the formation of liposomes, by the maintenance of therequired particle size in the case of dispersions, or by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars, buffers, or sodium chloride. Prolongedabsorption of the injectable compositions can be brought about by theuse in the compositions of agents delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the compoundsin the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, preferably followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the compounds may be applied in pure form.However, it may be desirable to administer them to the skin ascompositions or formulations, in combination with a dermatologicallyacceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Other solidcarriers include nontoxic polymeric nanoparticles or microparticles.Useful liquid carriers include water, alcohols, or glycols, orwater/alcohol/glycol blends, in which the compounds can be dissolved ordispersed at effective levels, optionally with the aid of non-toxicsurfactants. Adjuvants such as fragrances and additional antimicrobialagents can be added to optimize the properties for a given use. Theresultant liquid compositions can be applied from absorbent pads, usedto impregnate bandages and other dressings, or sprayed onto the affectedarea using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses, or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds to the skin are known to the art; for example, seeJacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S.Pat. No. 4,820,508), all of which are hereby incorporated by reference.

The concentration of the therapeutic compounds of the invention in suchformulations can vary widely depending on the nature of the formulationand intended route of administration. For example, the concentration ofthe compounds in a liquid composition, such as a lotion, can preferablybe from about 0.1-25% by weight, or, more preferably, from about 0.5-10%by weight. The concentration in a semi-solid or solid composition suchas a gel or a powder can preferably be about 0.1-5% by weight, or, morepreferably, about 0.5-2.5% by weight.

Effective dosages and routes of administration of agents of theinvention are conventional. The exact amount (effective dose) of theagent will vary from subject to subject, depending on, for example, thespecies, age, weight, and general or clinical condition of the subject,the severity or mechanism of any disorder being treated, the particularagent or vehicle used, the method and scheduling of administration, andthe like. A therapeutically effective dose can be determinedempirically, by conventional procedures known to those of skill in theart. See, e.g., The Pharmacological Basis of Therapeutics, Goodman andGilman, eds., Macmillan Publishing Co., New York. For example, aneffective dose can be estimated initially either in cell culture assaysor in suitable animal models. The animal model may also be used todetermine the appropriate concentration ranges and routes ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Methods for theextrapolation of effective dosages in mice and other animals to humansare known to the art; for example, see U.S. Pat. No. 4,938,949, which ishereby incorporated by reference. A therapeutic dose can also beselected by analogy to dosages for comparable therapeutic agents.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g., the subject, the disease, the disease state involved,and whether the treatment is prophylactic). Treatment may involve dailyor multi-daily doses of compound(s) over a period of a few days tomonths, or even years.

In general, however, a suitable dose will be in the range of from about0.001 to about 100 mg/kg of body weight per day, preferably from about0.01 to about 100 mg/kg of body weight per day, more preferably, fromabout 0.1 to about 50 mg/kg of body weight per day, or even morepreferred, in a range of from about 1 to about 10 mg/kg of body weightper day. For example, a suitable dose may be about 1 mg/kg, 10 mg/kg, or50 mg/kg of body weight per day.

The compounds are conveniently administered in unit dosage form; forexample, containing about 0.05 to about 10000 mg, about 0.5 to about10000 mg, about 5 to about 1000 mg, or about 50 to about 500 mg ofactive ingredient per unit dosage form.

The compounds can be administered to achieve peak plasma concentrationsof, for example, from about 0.25 to about 200 μM, about 0.5 to about 75μM, about 1 to about 50 μM, about 2 to about 30 μM, or about 5 to about25 μM. Exemplary desirable plasma concentrations include at least 0.25,0.5, 1, 5, 10, 25, 50, 75, 100 or 200 μM. For example, plasma levels maybe from about 1 to about 100 micromolar or from about 10 to about 25micromolar. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the compounds, optionally insaline, or orally administered as a bolus containing about 1 to about100 mg of the compounds. Desirable blood levels may be maintained bycontinuous or intermittent infusion.

The compounds may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, as onedose per day or as two, three, four or more sub-doses per day. Thesub-dose itself may be further divided, e.g., into a number of discreteloosely spaced administrations; such as multiple inhalations from aninsufflator.

All documents, references, and information, including, but not limitedto, journal articles, patent applications, and patents, that arementioned, cited, or referred to in this application are herebyincorporated by reference in their entirety as if each had beenindividually incorporated.

Example 1: Synthesis of a Compound of Formula I

A compound of Formula I was synthesized, from the compound of FormulaXIII (Scopolamine [51-34-3]) ((2S)-(1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl-3-hydroxy-2-phenylpropanoatehydrobromide trihydrate) by the steps described below in Schemes 1through 12.

A first step is illustrated in Scheme 1:

Inside a 10 liter four necked round bottom flask, sodium borohydride(172 g, 4558 mmol) was added portion wise over about 2 hours to amechanically stirred suspension of a compound of Formula XIII (333 g,760 mmol) in 3 liters of absolute ethanol in an ice bath. During thistime gas formation occurred and the suspension was stirred while beingwarmed to ambient temperature overnight. While being heated, atapproximately 10° C., sudden additional gas formation and foamingoccurred.

The milky suspension was then concentrated to about half of its originalvolume (i.e. from about 3 L to 1.5 L) with additional precipitateobserved, which yielded the batch. Meanwhile, 5 M HCl in isopropylalcohol (IPA) (5318 mmol, 1.064 L) was diluted with 2 L of technicaldiethyl ether (Et₂O). The obtained hydrochloric acid (HCl) solution wasthen added drop wise to the ice-chilled batch, while being stirred. Thewhite suspension was allowed to be mechanically stirred overnight toallow for full hydrolysis of the borate salts.

The reaction mixture was filtered and the resulting solid was rinsedtwice with 500 mL portions of Et₂O. The dried solid (which containedsome Et₂O) was dissolved in a minimum amount of 10% aqueous potassiumcarbonate (K₂CO₃) solution (˜1.5 L) until just a clear solution wasobtained. 200 mL of brine and ˜50 g solid NaCl was added to thesolution. The aqueous phase was then thoroughly extracted withchloroform/methanol (MeOH)/[7N NH₃ in MeOH] (85:14:1). This procedurewas performed 5 times with 1.0 L portions of this solvent mixture each.The combined organic extracts were dried (sodium sulphate (Na₂SO₄)),filtered and the solvent was removed under reduced pressure to give102.2 g (659 mmol) of a compound of Formula XII((1R,2R,4S,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol) as aslightly tan oil at 87% yield. ^(1H)NMR (CDCl₃) (FIG. 1) showedstructural agreement with the compound of Formula XII with minor amountsof impurities. ^(1H)NMR (400 MHz, Chloroform-d) δ 4.03-4.00 (m, 1H),3.67 (s, 2H), 3.20-3.18 (m, 2H), 2.52 (s, 3H), 2.14-2.08 (m, 2H),1.69-1.37 (m, 3H).

The next step proceeded as illustrated by Scheme 2:

To a solution of the compound of Formula XII (102.2 g, 659 mmol),benzoic acid (BzOH) (97 g, 790 mmol) and triphenylphosphine (PPh₃) (207g, 790 mmol) in 1000 mL of dry tetrahydrofuran (THF) a solution ofdiisopropyl azodicaboxylate (DIAD) (160 g, 790 mmol, 154 mL) in 100 mLof dry THF was added drop wise over a period of 4 hours. During theaddition the solution was kept between −35 and −25° C. using acetone/dryice. The clear, colorless solution was then removed from the ice bathand stirred at room temperature overnight.

Samples were taken and analyzed, and the analysis showed the reactionwent to completion. The reaction mixture was concentrated, dissolved in1 L of ethyl acetate (EtOAc), extracted with 1 L of saturated sodiumbicarbonate (NaHCO₃), and subsequently with aqueous 2 M HCl (1×1 L,2×0.5 L). The combined acidic aqueous fractions were washed once morewith 1 L of EtOAc. Approximately 400 g of potassium carbonate (K₂CO₃)was added portionwise to the acidic aqueous layer, while being stirred,until no more gas formation was observed. The pH of the resultingsolution was slightly basic and slightly turbid and yellow. The aqueousphase was then extracted with a dichloromethane (DCM)/MeOH 9:1 (3×, 1 Leach) solution and the combined organic fractions were dried with sodiumsulfate (Na₂SO₄), filtered and concentrated to afford 118.3 g (447 mmol)of a compound of Formula XI((1R,2R,4S,5S,7r)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ylbenzoate), which was then confirmed by MS (FIG. 2) to have 98% purity at67.9% yield. ^(1H)NMR (400 MHz, Chloroform-d) δ 8.07-7.93 (m, 2H),7.59-7.48 (m, 1H), 7.44-7.40 (m, 2H), 5.39-5.30 (m, 1H), 3.63 (s, 2H),3.42-3.25 (m, 2H), 2.57 (s, 3H), 2.10-2.04 (m, 2H), 1.92-1.86 (m, 2H).

The next step proceeded as illustrated in Scheme 3:

To a solution of the compound of Formula XI (201.9 g, 779 mmol) inchloroform (350 mL) under a nitrogen atmosphere (not a stream), K₂CO₃(452 g, 3270 mmol) and ethyl chloroformate (279 g, 2569 mmol, 247 mL)were added to form a light yellow suspension which was then stirredunder reflux overnight.

A sample was then taken and analyzed to show that the reaction hadreached a 74% conversion to the product, a compound of Formula X(1R,2R,4S,5S,7r)-ethyl 7-(benzoyloxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate). The mixture was further stirred at refluxtemperature for another 24 hours.

Another sample was then taken and analyzed which showed that thereaction had reached a 75% conversion to product. In order to drive thereaction toward completion, additional K₂CO₃ (53.8 g, 389 mmol) andethyl chloroformate (85 g, 779 mmol, 74.8 mL) were added to the reactionsolution and the mixture was stirred at reflux temperature overnight.

After being stirred and refluxed overnight, another sample was takenwhich was analyzed to show that the reaction had reached a 81%conversion to the compound of Formula X.

The reaction mixture was then diluted with 500 mL of DCM and the organiclayer was washed with 750 mL of a half saturated aqueous NaHCO₃solution, 750 mL of 0.4 M aqueous HCl, and 750 mL of brine. The mixturenext dried over Na₂SO₄, then filtered and concentrated under reducedpressure which then afforded a yellow oil. 300 mL of Heptane was addedand the mixture was vigorously stirred overnight.

A white suspension had formed which contained big white lumps which werecrushed with a spatula. The suspension was filtered over a glass filter,rinsed with approximately 250 mL of heptane and approximately 200 mL ofpentane. The suspension was then dried using a vacuum oven for 3 hoursyielding the compound of Formula X as a white solid (219.6 g, 692 mmol,89% yield). LCMS of the product showed a percent yield greater than 95%,with a mass and structure agreement with the desired product as shown inthe MS (FIG. 3B) and ^(1H)NMR (FIG. 3A)). ^(1H)NMR (400 MHz,Chloroform-d) δ 8.01-7.97 (m, 2H), 7.61-7.53 (m, 1H), 7.48-7.42 (m, 2H),5.48-5.39 (m, 1H), 4.58 (m, 1H), 4.48 (m, 1H), 4.16 (q, J=7.1 Hz, 2H),3.56-3.53 (m, 2H), 2.34-2.21 (m, 2H), 1.98-1.86 (m, 2H), 1.27 (t, J=7.1Hz, 3H).

The next step proceeded as illustrated in Scheme 4:

In a 6 L three necked flask, sodium borohydride (157 g, 4152 mmol) wasadded to a suspension of the compound of Formula X (219.6 g, 692 mmol)in 1.5 L of absolute ethanol at room temperature. The reaction wasexothermic, and had an internal temperature greater than 60° C. over aperiod of approximately 4 hours, during the reaction extreme gas/foamformation was observed. The suspension was magnetically stirred at 50°C. overnight.

A sample was then taken and analyzed by TLC to show that the reactionhad gone to completion. The resulting product was a white solid whichstopped the magnetic stirrer during the night. The mixture wasconcentrated under reduced pressure and the white solid residue waspartitioned between 1 L of chloroform and 3.5 L of half-saturatedaqueous NaHCO₃ solution. The layers were next separated and the aqueouslayer was extracted with additional chloroform (2×, 1 L each). Thecombined organic layers were washed with 1 L of brine, dried overNa₂SO₄, and filtered and concentrated under reduced pressure to affordapproximately 220 g of the product as a white solid which was stirred in0.6 L of heptane overnight with a magnetic stirrer.

The mixture was then filtered off, the product had formed spheres whichwere crushed and had 500 mL of heptane added to them. The mixture wasstirred vigorously overnight with a magnetic stirrer.

After stirring the mixture overnight, the off-white suspension stillcontained spheres which then were crushed with a spatula. The suspensionwas filtered and the residue was rinsed with approximately 300 mLheptane and dried by vacuum which yielded approximately 148 g of theproduct. A sample was taken and analysed by ^(1H)NMR to show thestructure was in agreement with the compound of Formula IX(1R,2R,4S,5S,7r)-ethyl7-hydroxy-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate), (FIG.4).

The residue was stirred in approximately 300 mL of Et₂O for 1 hour. Thewhite suspension was filtered; and the residue was rinsed again withapproximately 300 mL of Et₂O and then dried by vacuum (under N₂-flow) toyield the compound of Formula IX (122 g, 572 mmol, 82% yield). ^(1H)NMR(400 MHz, Chloroform-d) δ 4.50 (m, 1H), 4.41 (m, 1H), 4.23-4.09 (m, 3H),3.42-3.39 (m, 2H), 2.15-2.08 (m, 2H), 1.73-1.62 (m, 2H), 1.44 (d, J=5.9Hz, 1H), 1.26 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 5:

Triethylamine (22.78 g, 225 mmol, 31.4 mL) and mesyl-Cl (23.64 g, 206mmol, 16.08 mL) was added drop wise to a solution of the compound ofFormula IX (40 g, 188 mmol) in DCM (500 mL) at 0° C. Once the additionwas complete, the ice bath was removed and the slightly milky suspensionwas stirred while warming to room temperature.

After 1 hour a sample was taken and analyzed by TLC which showed fullconversion had occurred. The reaction mixture was then washed twice with500 mL of water. The DCM layer appeared milky and was dried over Na₂SO₄(which made the layer clearer), and then filtered and concentrated underreduced pressure to afford a thick oil. The oil was stripped twice withtoluene to afford 54.2 g of a light tan solid which contained 21 w %toluene.

The solid was further dried under vacuum at 50° C. until the weightremained constant at 43.2 g (148 mmol; 78.9% yield) yielding a compoundof Formula VIII ((1R,2R,4S,5S,7r)-ethyl 7-((methylsulfonyl)oxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate). Asample was taken and the structure was confirmed by ^(1H)NMR (FIG. 5).^(1H)NMR (400 MHz, Chloroform-d) δ 5.11-5.02 (m, 1H), 4.54-4.53 (m, 1H),4.44-4.43 (m, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.47-3.45 (m, 2H), 3.00 (s,3H), 2.28-2.23 (m, 2H), 2.00-1.90 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 6:

Potassium cyanide (12.14 g, 186 mmol) and 18-crown-6(1,4,7,10,13,16-hexaoxacyclooctadecane) (0.493 g, 1.864 mmol) were addedto a solution of the compound of Formula VIII (19.89 g, 62.1 mmol, 91%)in 300 mL of dry Dimethyl sulfoxide to form a pale yellow solution whichwas stirred at 65° C. for two and a half days, or approximately 65hours, to yield a light brown solution. A sample was taken and analyzedby TLC (heptane/DME 1:1, molybdate staining required), which showed aclean conversion to the desired product (no exo-epimeric sideproductobserved), however, the reaction had not run to completion as startingmaterial was also observed.

The stirring was continued for a total of 118 hours, after which thebrown solution was allowed to cool to room temperature, and combinedwith an additional batch before being partitioned between 2 L of EtOAcand 2 L of water. The layers were separated and the organic layer waswashed twice with 1 L of brine, dried over Na₂SO₄, and filtered andconcentrated under reduced pressure to afford the crude product, acompound of Formula VII ((1R,2R,4S,5S,7s)-ethyl7-cyano-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate).

The resulting product was purified by gravity column chromatography (750g silica, heptane/[5→50% EtOAc]) to afford 15.1 g of a white solid, or acompound of Formula VII. A sample was taken and analyzed by ^(1H)NMR(FIG. 6) which demonstrated the product was in agreement with thestructure of Formula VII, although the product did contain 10 w % of theexo-sideproduct (which was not problematic for the follow-up reactions)and 7.5 w % of heptane. The combined yield from all experiments was 7.55g, or 45% yield, after correction for solvent and side product content.^(1H)NMR (400 MHz, Chloroform-d) δ 4.53-4.52 (m, 1H), 4.43-4.41 (m, 1H),4.12 (q, J=7.1 Hz, 2H), 3.70-3.68 (m, 2H), 2.93-2.89 (m, 1H), 2.22-2.12(m, 2H), 2.04-1.98 (m, 2H), 1.24 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 7:

A 50% slurry of Raney-nickel in water was added to a solution of thecompound of Formula VII (18.20 g, 82 mmol) in 350 mL of MeOH/200 mL ofammonia (7N in MeOH). The solution was kept under a nitrogen atmosphereand the Raney-nickel slurry was added until a dark black suspension wasobtained while being stirred vigorously. The reaction vessel wasevacuated and refilled with H₂ balloons, which was repeated twice, andthen stirred at 45° C. under a H₂ atmosphere created by the balloons.After 3 hours, a sample was taken and analyzed by TLC usingheptane/dimethoxyethane (DME) 1:1, which demonstrated the reaction wascomplete.

The reaction mixture was filtered over a short pad of celite which waspre-rinsed with MeOH. The residue was also rinsed with additional MeOH.The filtrate was concentrated under reduced pressure to give a lightyellow oil. This crude product consisted mainly of the open amines of acompound of Formula VI.a (1R,2R,4S,5S,7s)-ethyl7-(aminomethyl)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate andto a lesser extent the (desired) cyclized amine a compound of Formula VI(rac-(2R,3 S,6 S,7aS)-ethyl3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).

To drive cyclization of the main endo-isomer to completion, theintermediate was dissolved in 500 mL of absolute ethanol, which createda light yellow solution, which was then stirred and refluxed overnight.A sample was taken, concentrated under reduced pressure, dissolved inCDCl₃, and analyzed by ^(1H)NMR (FIG. 7) which showed the intermediate,open endo-isomer, had cyclized. It was further shown that approximately9% of the product was open exo-amine, and some solvent remained.^(1H)NMR (400 MHz, Chloroform-d) δ 4.46-4.01 (m, 5H), 3.50-3.44 (m, 1H),3.16-3.11 (m, 1H), 3.96-2.93 (m, 1H), 2.10-1.66 (m, 5H), 1.47 (d, J=13.3Hz, 1H), 1.26 (t, J=7.1 Hz, 3H).

The main batch, a yellow solution, was concentrated under reducedpressure and the residue was redissolved in 500 mL of CHCl₃ and driedover Na₂SO₄. The solution was filtered and concentrated to give 21.7 gof a compound of Formula VI as a thick yellow oil which containedsolvent and the open exo-amine which was used in the next step.

The next step proceeded as illustrated in Scheme 8:

Benzaldehyde (22.74 g, 214 mmol, 21.72 mL) was added to a solution ofthe compound of Formula VI (37.3 g, 165 mmol) in 1000 mL ofdichloromethane. After 15 minutes STAB (55.9 g, 264 mmol) was added. Thesuspension was then stirred at room temperature overnight.

The reaction mixture was washed with 1 L of water and 1 L NaHCO₃. Theorganic layer was dried with Na₂SO4₂ and concentrated to dryness toafford 55 g of the reacted product, which was next purified by gravitycolumn chromatography (“600 g, Hep/5-60% ETOAc) affording: 2.2 g ofexo-Bn2N-adduct; and 35.3 g of a compound of Formula V (rac-(2R,3 S,6S,7aS)-ethyl3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as analyzed and confirmed by ^(1H) NMR (FIG. 8B) and MS (FIG. 8A).^(1H)NMR (400 MHz, Chloroform-d) δ 7.35-7.30 (m, 4H), 7.26-7.22 (m, 2H),4.41-4.02 (m, 5H), 3.83-3.78 (m, 1H), 3.66 (d, J=13.3 Hz, 1H), 3.30-3.26(m, 1H), 3.11-3.06 (m, 1H), 2.35-2.31 (m, 1H), 2.07-1.88 (m, 3H),1.77-1.65 (m, 2H), 1.44 (d, J=13.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H).

The next step proceeded as illustrated in Scheme 9:

Imidazole (15.19 g, 223 mmol) and tert-butyldiphenylchlorosilane (30.7g, 112 mmol, 28.7 mL) were added to a solution of the compound ofFormula V (35.3 g, 112 mmol) in 100 mL of dry N,N-dimethylformamide toform a pale yellow solution which was stirred at room temperatureovernight.

After the stirring was complete a sample was taken and analyzed by LCMSwhich showed the reaction was complete.

The solution was then concentrated under reduced pressure to yield anoily residue which was diluted with 750 mL of DCM and washed with 750 mLof 1:1 saturated aqueous NaHCO₃ solution and water. Next the solutionwas washed with 750 mL of brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated to afford approximately 65 g of thereacted product as confirmed by TLC.

The reacted product was purified by gravity column chromatography(approximately 600 g, Hep/5-15% EtOAc) which afforded 59.5 g, or a 90%yield, of a compound of Formula IV (rac-(2R,3R,6S,7aS)-ethyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)as a very thick colorless oil. A sample was taken and analyzed by^(1H)NMR (FIG. 9B) and LCMS (FIG. 9A), which showed the product was inagreement with the structure of Formula IV and contained 6 w/w %heptane. ^(1H)NMR (400 MHz, Chloroform-d) δ 7.72-7.66 (m, 4H), 7.47-7.36(m, 6H), 7.26-7.16 (m, 3H), 7.12-7.09 (m, 2H), 4.62-4.48 (m, 1H), 4.26(s, 1H), 4.22-4.03 (m, 3H), 3.40-3.29 (m, 2H), 2.89-2.78 (m, 2H),1.92-1.76 (m, 4H), 1.62-1.52 (m, 1H), 1.31-1.23 (m, 3H), 1.17-1.11 (m,1H), 1.02 (s, 9H).

The next step proceeded as illustrated in Scheme 10:

Iodotrimethylsilane (75.0 g, 375 mmol, 51 ml) was added to a solution ofthe compound of Formula IV (73.9 g, 124 mmol, 93%) in 1.2 L of drytoluene to create a yellow reaction mixture which was stirred at 85° C.overnight.

A sample taken then taken and analyzed by TLC, which showed the reactionhad gone to completion. The resulting reaction mixture was a darksolution, and was allowed to cool to room temperature (suspension) andquenched with 250 mL of MeOH. The mixture was next concentrated toapproximately 250 mL. After which 750 mL of DCM was added and themixture was washed with 750 mL of 1:1 saturated aqueous NaHCO₃solution/H₂O. The organic layer was then washed with 750 mL of brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford approximately 72 g, or a 92% yield, of a compound of Formula III(rac-(2R,3R,6S,7aS)-4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine) as a dark yellow/orangeoil.

A sample was taken and analyzed by LCMS (FIG. 10) which showed thecorrect mass, and that the product had a purity of about 80%, with thepeak at 0.448 being toluene. ^(1H)NMR (400 MHz, Chloroform-d) δ7.69-7.63 (m, 4H), 7.47-7.37 (m, 6H), 7.26-7.12 (m, 5H), 4.36 (s, 1H),3.73-3.70 (m, 1H), 3.39 (d, J=13.7 Hz, 1H), 3.26 (d, J=7.6 Hz, 1H), 3.06(s, 1H), 2.90 (d, J=13.7 Hz, 1H), 2.79-2.74 (m, 1H), 2.41 (bs, 1H),1.90-1.80 (m, 4H), 1.67-1.64 (m, 1H), 1.11-0.99 (m, 10H).

The next step proceeded as illustrated in Scheme 11:

Et₃N (48.3 g, 477 mmol, 0.067 L) and di-tert-butyl dicarbonate (Boc₂O)(39.1 g, 179 mmol) was added to a solution of the compound of FormulaIII (72 g, 119 mmol, 80%) in 1 L of dichloromethane to form a lightyellow solution which was stirred at room temperature over the weekend.

A sample taken and analyzed by TLC which showed the reaction wascomplete. The solution was diluted with 250 mL of DCM and washed with 1L of saturated aqueous NaHCO₃ solution and 1 L of brine. The organiclayer was then dried over Na₂SO₄, filtered, and concentrated to affordapproximately 80 g of the crude product. Purification by gravity columnchromatography (800 g, heptane/[EtOAc 1→10%]) afforded 68.4 g, or a 94%yield, of a compound of the Formula II (rac-(2R,3R,6S,7aS)-tert-butyl4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate) as a colorless glass. Asample was taken and analyzed by ^(1H)NMR (FIG. 11A) and LCMS (FIG. 11B)which showed agreement between the product and the structure of FormulaII, and further showing that the product contained 4 w/w % heptane.^(1H)NMR (400 MHz, Chloroform-d) δ 7.73-7.65 (m, 4H), 7.47-7.35 (m, 6H),7.24-7.10 (m, 5H), 4.53-4.40 (m, 1H), 4.24 (d, J=3.8 Hz, 1H), 4.10-3.92(m, 1H), 3.44-3.32 (m, 2H), 2.87 (d, J=13.6 Hz, 1H), 2.33-2.77 (m, 1H),1.93-1.72 (m, 4H), 1.65-1.54 (m, 1H), 1.50-1.47 (m, 9H), 1.10-1.02 (m,10H).

The next step proceeded as illustrated in Scheme 12:

Under a nitrogen flow, Palladium, 10% on activated carbon (7 g, 125mmol) was added to a solution of the compound of Formula II (72.9 g, 125mmol) in 600 mL of acetic acid. The vessel was closed and the resultingmixture was stirred at 50° C. for 2 hours under a hydrogen atmospherecreated by a balloon.

The mixture was then stirred at 50° C. overnight. The black suspensionwas filtered over EtOH rinsed celite and the filtrate was concentratedunder reduced pressure. The residue was stripped twice with 0.5 L oftoluene, after which it was dissolved in 1 L of diethyl ether. Theorganic layer was washed with 1 L of 10% (w/v) aqueous K₂CO₃ solution, 1L of brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure before being stripped again with pentane to afford 58.5 g of athick tan syrup, a compound of Formula I (rac-(2R,3S,6S,7aS)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate).A sample was taken and analyzed by ^(1H)NMR (FIG. 12B) and LCMS (FIG.12A) which showed the product was in agreement with structure of FormulaI and contained 5.1 weight % of toluene and 1.3 weight % of n-pentane.^(1H)NMR (400 MHz, Chloroform-d) δ 7.68-7.63 (m, 4H), 7.45-7.35 (m, 6H),4.40-4.25 (m, 1H), 4.13-3.93 (m, 2H), 3.41-3.36 (m, 1H), 2.97-2.92 (m,1H), 2.62 (d, J=11.5 Hz, 1H), 1.96-1.78 (m, 2H), 1.67 (s, 1H), 1.64-1.56(m, 1H), 1.49-1.47 (m, 9H), 1.16-1.13 (m, 1H), 1.05-1.04 (m, 9H).

The compound of Formula I was separated into its respective enantiomersvia supercritical fluid chromatography (SFC) on a Welkho-1 column with90/10 scCO₂/iPrOH+0.2% isopropylamine eluent as illustrated in Scheme13:

An overview of these synthetic steps to transform the starting reactantinto a compound of Formula I is provided in Scheme 14:

Example 2: Synthesis of a Therapeutic Derivative of a Compound ofFormula I

The following describes steps for synthesizing a compound of FormulaXVIII from a compound of Formula I.a.

As illustrated below in Scheme 15, first the compound of Formula XIV((2R*,3R*,3 aS*,6S*,7aS*)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate), wassynthesized from the compound of Formula I.a.

11.58 g (30.4 mmol) of1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) was added to a solution of5-fluoropicolinic acid (4.30 g, 30.4 mmol) and diisopropylethylamine(DIPEA) (3.93 g, 30.4 mmol, 5.32 mL) in 125 mL of DCM. The reactionmixture was stirred then for 2 hours at room temperature. A solution ofthe compound of Formula I.a (12.5 g, 25.4 mmol) in 125 mL of DCM wasadded, and the reaction mixture was stirred overnight at roomtemperature.

The reaction mixture was diluted with 200 mL of DCM, washed with aqueoussaturated NaHCO₃ (300 mL), 1 M KHSO₄ (300 mL) and brine (400 mL). Theorganic layer was dried with sodium sulfate and concentrated to yield22.0 g, (141%) of the compound of Formula XIV, as confirmed by LCMS(FIG. 13).

As illustrated below in Scheme 16, a compound of Formula XV ((2R*,3R*,3aS*,6S*,7aS*)-tert-butyl4-(5-fluoropicolinoyl)-3-hydroxyoctahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)was then synthesized from the compound of Formula XIV.

To a solution of the compound of Formula XIV (15.64 g, 25.4 mmol) in 100mL of dry tetrahydrofuran was added 76 mL (76 mmol) tetrabutylammoniumfluoride (TBAF) and the reaction mixture was stirred at 50° C.overnight. The reaction mixture was concentrated to dryness and purifiedby gravity column chromatography (500 mL silica, DCM to 5% MeOH/DCM) toyield 11.4 g of desired material, contaminated with side products. Theresidue was dissolved in 0.25 L of EtOAc and washed twice with 0.5 L ofbrine to yield 9.50 g (99%) of the compound of Formula XV, contaminatedwith an unidentified impurity, as indicated by LCMS Analysis (FIG. 14).The material was used as such in the next reaction.

As illustrated below in Scheme 17, a compound of Formula XVI ((2R*,3R*,3aS*,6S*,7aS*)-tert-butyl3-((cyclopropanecarbonyl)oxy)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)was then synthesized from the compound of Formula XV.

The compound of Formula XV (3.5 g, 9.27 mmol) was dissolved in 40 mL ofpyridine, followed by the addition of 1.133 g (9.27 mmol) of4-dimethylaminopyridine (DMAP) and 20.16 mL (23.18 mmol) ofcyclopropanecarbonyl chloride. The reaction mixture was stirred at 60°C. for 3 hours. Afterwards, the reaction mixture was diluted with 250 mLof ethyl acetate and washed with KHSO₄ (0.5M, 200 mL), NaHCO₃. (sat.,aq., 200 mL) and brine (200 mL). The organic phase was dried with sodiumsulfate, filtered and the solvent evaporated. The crude residue waspurified by gravity column chromatography (silica, 50% EtOAc/heptane to100% EtOAc) to yield 3.40 g (82%) of the compound of Formula XVI, asconfirmed by LCMS (FIG. 15).

As illustrated below in Scheme 18, a compound of Formula XVII((2R*,3R*,3aS*,6S*,7aS*)-4-(5-fluoropicolinoyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-3-ylcyclopropanecarboxylate) was then synthesized from the compound ofFormula XVI.

In a 250 mL round-bottomed flask, 3.40 g (7.63 mmol) of the compound ofFormula XVI was dissolved in 30 mL of DCM. Trifluoroacetic acid (46.1 g,404 mmol, 30 ml) was added and the reaction mixture was stirred at roomtemperature for 90 minutes. The reaction mixture was evaporated todryness and co-evaporated twice with toluene. This residue waspartitioned between 150 mL of CHCl₃ and 150 mL of saturated Na₂CO₃(aq),and the organic phase was separated. The aqueous layer was extractedtwice with 100 mL of CHCl₃. The combined organic layers were washed with100 mL of brine, dried over Na₂SO₄, filtrated, evaporated to dryness andco-evaporated with DCM once to yield 2.791 g (106%) of the compound ofFormula XVII, as confirmed by LCMS analysis (FIG. 16)

As illustrated below in Scheme 19, a compound of Formula XVIII wassynthesized from the compound of Formula XVII.

The compound of Formula XVII was dissolved in 2 mL of DCM, followed bythe addition of piperonal (1.3 eq: 36.17 mg; 0.24 mmol). After stirringfor 2 hours at room temperature, 64.80 mg (0.31 mmol) of STAB was added.The reaction mixture was stirred overnight at room temperature,evaporated to dryness, and purified by preparative HPLC to yield 68.4 mg(77%) of the compound of Formula XVIII, as confirmed by LCMS (FIG. 17A)and ^(1H)NMR (FIG. 17B).

Example 3: Synthesis of a Second Therapeutic Derivative of a Compound ofFormula I

The following describes steps for synthesizing a compound of FormulaXXII from a compound of Formula I.b.

As illustrated below bin Scheme 20, first the compound of Formula XIX((2S*,3S*,6R*,7aR*)-tert-butyl3-((tert-butyldiphenylsilyl)oxy)-4-(2-methoxyacetyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)was synthesized from the compound of Formula I.b.

3.17 g (35.2 mmol, 2.70 mL) of 2-methoxyacetic acid was dissolved in 124mL of DCM and 4.55 g (35.2 mmol, 6.14 mL) of DIPEA. Then 13.40 g (35.2mmol) of HATU was added and the mixture was stirred at ambienttemperature for 2 hours. A solution of 12.4 g (25.2 mmol) of thecompound of Formula I.b in 125 mL of DCM was added and stirred atambient temperature overnight.

The reaction mixture was washed with aqueous saturated NaHCO₃ (200 mL),1M aqueous KHSO₄ (200 mL), water (200 mL) and brine (200 mL), theorganic phase was dried with Na₂SO₄, filtered and the solvent evaporatedto yield 23.40 g of the crude product, the compound of formula XIX.HPLC/MS analysis (FIG. 18) indicates that the desired material wascontaminated with residual DIPEA.

As illustrated below in Scheme 21, a compound of Formula XX((2S*,3S*,3aS*,6R*,7aR*)-tert-butyl3-hydroxy-4-(2-methoxyacetyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridine-1-carboxylate)was then synthesized from the compound of Formula XIX.

To a solution of the compound of Formula XIX (14.23 g, 25.2 mmol) in 100mL of dry tetrahydrofuran (THF), at ambient temperature, a 1.0 Msolution of tetrabutylammonium fluoride (TBAF) in THF (76 mmol, 76 mL)was added to the solution. The reaction mixture was then heated to 50°C. and stirred overnight. The crude reaction mixture was concentrated todryness, and stripped twice with a 1:1 solution of ethylacetate/heptaneto yield 23.40 g of the crude material. Purification by gravity columnchromatography 50-100% ethylacetate in heptane yielded 8.21 g(quantitatively) of the compound of formula XX, as confirmed by LCMSanalysis (FIG. 19).

As illustrated below in Scheme 22, a compound of Formula XXI(1-((2S*,3S*,3aS*,6R*,7aR*)-3-hydroxyhexahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-4(2H)-yl)-2-methoxyethanone)was then synthesized from the compound of Formula XX.

To a solution of the compound of Formula XX (1.89 g, 5.79 mmol) in 35 mLof DCM was added to 51.8 g (454 mmol, 35 mL) trifluoroacetic acid (TFA)and the reaction mixture was stirred at room temperature for 1.5 hours.The reaction mixture was evaporated to dryness under reduced pressureand coevaporated twice with toluene. The resulting sticky oil wasdissolved in 35 mL of chloroform and washed with aqueous saturatedNa₂CO₃. Attempts to isolate the desired material in the organic phasewere not successful. The aqueous phase was then evaporated to drynessunder reduced pressure.

To the solid was added a 9:1 mixture of chloroform/MeOH and thesuspension was stirred overnight at room temperature. After filtration,the filtrate was evaporated to dryness under reduced pressure. Theresulting solid was dissolved in chloroform, filtered (using a 40 micronLCMS filter) and evaporated to dryness under reduced pressure to afford0.91 g, or 69.5% yield, of the compound of Formula XXI as a white foam,which was confirmed by LCMS (FIG. 20). The product was then used as suchin the next reaction.

As illustrated in Scheme 23, a compound of Formula XXII(3-(((2S*,3S*,6R*,7aR*)-3-hydroxy-4-(2-methoxyacetyl)octahydro-1H-2,6-methanopyrrolo[3,2-b]pyridin-1-yl)methyl)benzamide)was synthesized from the compound of Formula XXI.

To a solution of the compound of Formula XXI (193 mg; 0.85 mmol) in 2 mLof DCM was added 165.4 mg (1.11 mmol) of 3-formyl benzamide and thereaction mixture was stirred overnight. Next, to the reaction mixturewas added 298.3 mg (1.141 mmol) sodium triacetoxyborohydride and thereaction mixture was stirred at room temperature overnight. The reactionmixture was evaporated to dryness under reduced pressure using aGenevac. Purification by prep LCMS followed by evaporation of thesolvents under reduced pressure (Genevac) afforded 244 mg, a 79.6%yield, of the desired product, the compound of Formula XXII, asconfirmed by LCMS (FIG. 21A) and ^(1H)NMR (FIG. 21B).

Example 4: Therapeutic Evaluation of Compounds of Formula XVIII and XXII

Intra plantar injection of 1% β-carrageenan may be used to induce localinflammation to the paws of test subject mice. In general, localinflammation is expressed as paw swelling and increased sensitivity toheat stimuli. Therefore, the effect of a test item on changes in heathypersensitivity can be assessed. Using the protocol set forth, thetherapeutic effect of the compounds of Formula XVIII and XXII wereevaluated.

Animals were dosed with a test compound at time zero (control wheregiven vehicle only) at 10 mg/kg ip (test item was dissolved in a 20%λ-hydroxypropyl cyclodextrin solution). After 30 minutes the animalswere slightly anesthetized with isoflurane, and 0.1 ml of a 1%λ-carrageenan suspension in Distilled Water was injected into theplantar side of the right hind paws of the mice. After 3.5 hours afterthe λ-carrageenan administration, the animals were placed on a hotplateapparatus maintained at 57° C., and the time until the first responsewas recorded.

When the compound of Formula XVIII and the compound Formula XXII weretested as described above (n=5 animals), the average response timeexceeded the pretreatment baseline response time as shown below.

In contrast, vehicle-treated animals displayed reduced response timesover pre-treatment.

Pretreatment response time at Response time at Animal # (−24 h) (in sec)3.5 h (in sec) Vehicle 20% CD 1 9 3 2 7 4 3 8 4 4 7 6 5 10 5 avg 8.2 4.4Compound of 1 6 12 Formula XXII 2 8 14 3 8 13 4 6 10 5 9 12 avg 7.4 12.2Compound of 1 7 16 Formula XVIII 2 9 14 3 8 16 4 9 12 5 7 15 avg 8 14.6

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. All examples presented are representative and non-limiting.The above-described embodiments of the invention may be modified orvaried, without departing from the invention, as appreciated by thoseskilled in the art in light of the above teachings. It is therefore tobe understood that, within the scope of the claims and theirequivalents, the invention may be practiced otherwise than asspecifically described.

It should be understood that although the compounds of Formulas II-XXIIImay be drawn with specific chirality for the sake of simplicity, oneskilled in the art would recognize how to create and separate thesevarious isomers. Accordingly, all isomers of the compounds of FormulasII-XXIII may be understood to be within the scope of the presentapplication.

What is claimed is:
 1. A compound of Formula XXIII:

wherein: R₁ is tert-butyldiphenylsilyl, benzyl or hydrogen; R₂ is benzylor hydrogen; and R₃ is COOR₄, BOC, or hydrogen, wherein R₄ is selectedfrom the group consisting of alkyl and benzyl, or a stereoisomers,pharmaceutically acceptable salt, or mixture thereof.
 2. The compound ofclaim 1, wherein R₄ is benzyl or an alkyl having 1 to 8 carbon atoms. 3.The compound of claim 1, wherein R₄ is ethyl or tert-butyl.
 4. Acompound having the Formula XXII:

or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.5. A compound of the Formula I

or a stereoisomer, pharmaceutically acceptable salt, or mixture thereof.6. A pharmaceutical composition comprising a compound of anyone one ofclaims 1, 4, or 5, and a pharmaceutically acceptable carrier or diluent.7. A method for treating a subject suffering from pain, comprisingadministering to the subject an effective amount of the compound ofclaim
 4. 8. The method of claim 7, wherein the compound is administeredto effect localized delivery to the subject.
 9. The method of claim 7,wherein the compound is administered to effect systemic delivery to thesubject.
 10. The method of claim 7, wherein the pain is neuropathic painor chronic pain.
 11. The compound of claim 5, wherein the compound hasthe Formula I.
 12. The compound of claim 5, wherein the compound has theFormula II.
 13. The compound of claim 5, wherein the compound has theFormula III.
 14. The compound of claim 5, wherein the compound has theFormula IV.
 15. The compound of claim 5, wherein the compound has theFormula V.
 16. The compound of claim 5, wherein the compound has theFormula VI.